This invention relates to new hydrate and crystalline forms of alendronate sodium, processes for the manufacture thereof, and pharmaceutical compositions thereof.
Alendronate sodium, the sodium salt of alendronic acid, also known as 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium, has the formula I: 
It is an agent for combating bone resorption in bone diseases including osteoporosis and Paget""s disease.
Various methods for preparing alendronic acid are known in the art and have been disclosed in M. I. Kabachnik et al., Synthesis and Acid-Base and Complexing Properties of Amino-Substituted xcex1-Hydroxyalkylidene-diphosphonic Acids, Izv. Akad. Nauk USSR, Ser. Khim, 2,433 (1978) and in U.S. Pat. Nos. 4,407,761, 4,621,077, 4,705,651, 5,039,819 and 5,159,108.
U.S. Pat. No. 4,922,007 describes the preparation of a trihydrate of alendronate sodium by reaction of 4-aminobutyric acid with phosphorous acid and phosphorous trichloride in the presence of methanesulfonic acid followed by the addition of sodium hydroxide.
The present invention provides new forms of alendronate sodium, having water content of 1.3 to 11.7 percent, and processes for their manufacture. Moreover, the present invention provides new crystalline forms of alendronate sodium, designated forms B, D, E, F, G and H, and processes for the manufacture thereof.
The present invention provides novel hydrate forms of alendronate sodium having water content of between 1.3 and 11.7 percent water. Typically, but without limitation, the present invention relates to the following novel hydrate forms of alendronate monosodium: 1/4 hydrate, 1/3 hydrate, hemihydrate, 2/3 hydrate, 3/4 hydrate, monohydrate, 5/4 hydrate, 4/3 hydrate, 3/2 hydrate, 5/3 hydrate, 7/4 hydrate and dihydrate.
The present invention provides a new crystalline Form B of alendronate sodium, having a powder X-ray diffractogram substantially as depicted in FIG. 1a, with characteristic peaks at 12.2xc2x10.2, 13.3xc2x10.2, 14.8xc2x10.2, 15.8xc2x10.2, 16.3xc2x10.2, 16.6xc2x10.2, 17.2xc2x10.2, 19.4xc2x10.2, 21.3xc2x10.2, 22.6xc2x10.2, 23.2xc2x10.2, 24.0xc2x10.2, 25.2xc2x10.2, 25.8xc2x10.2, 27.4xc2x10.2, 29.4xc2x10.2, and 36.0xc2x10.2 degrees 2 theta. Alendronate sodium Form B has significant IR bands as depicted in FIG. 1c at 654 cmxe2x88x921, 955 cmxe2x88x921, 1074 cm-1, 1261 cmxe2x88x921, 1309 cmxe2x88x921, and 1614 cmxe2x88x921. The TGA curve, FIG. 1b, shows a clear two-step loss on drying of 7.2%, which implies that the crystal form B contains a stoichiometric quantity of water close to that of the monohydrate (expected loss on drying value: 6.2%).
Another embodiment of the invention is a new crystalline Form D of alendronate sodium, having a powder X-ray diffractogram substantially as depicted in FIG. 4a, with characteristic peaks at 13.1xc2x10.2, 15.2xc2x10.2, 16.3xc2x10.2, 18.4xc2x10.2, 20.8xc2x10.2, 22.3xc2x10.2, 22.5xc2x10.2, 23.4xc2x10.2, 23.7xc2x10.2, 31.4xc2x10.2, and 35.7xc2x10.2 degrees 2 theta. Form D as depicted in FIG. 4c has significant IR bands at 662 cmxe2x88x921, 919 cmxe2x88x921, 934 cmxe2x88x921, 954 cmxe2x88x921, 1054 cmxe2x88x921, 1072 cmxe2x88x921 1297 cmxe2x88x921 and 1318 cmxe2x88x921. The TGA curve, as depicted in FIG. 4b, shows a gradual loss on drying of 4.1% up to 180xc2x0 C.
An additional embodiment is a new crystalline Form E of alendronate sodium, having a powder X-ray diffractogram substantially as depicted in FIG. 5a, with characteristic peaks at 7.0xc2x10.2, 9.3xc2x10.2, 11.8xc2x10.2, 13.3xc2x10.2, 14.0xc2x10.2, 15.3xc2x10.2, 16.2xc2x10.2, 19.4xc2x10.2 degrees 2 theta. Form E has significant IR bands as depicted in FIG. 5c at 660 cmxe2x88x921, 897 cmxe2x88x921, 924 cmxe2x88x921, 953 cmxe2x88x921, 970 cmxe2x88x921, 1017 cmxe2x88x921, 1040 cmxe2x88x921, 1093 cmxe2x88x921 1149 cmxe2x88x921, 1177 cmxe2x88x921, 1252 cmxe2x88x921 1293 cmxe2x88x921 1337 cmxe2x88x921, 1535 cmxe2x88x921, 1606 cmxe2x88x921, and 1639 cmxe2x88x921. The TGA curve, as depicted in FIG. 5b, shows a gradual loss on drying of 3.7% up to 150xc2x0 C.
A still further embodiment of the invention is a new crystalline Form F of alendronate sodium, having a powder X-ray diffractograrn substantially as depicted in FIG. 6a, with characteristic peaks at 9.3xc2x10.2, 11.7xc2x10.2, 13.0xc2x10.2, 13.4xc2x10.2, 14.2xc2x10.2, 15.3xc2x10.2, 16.2xc2x10.2, 17.4xc2x10.2, 19.1xc2x10.2, 19.4xc2x10.2 and 25.5xc2x10.2 degrees 2 theta. Form F has significant IR bands as depicted in FIG. 6c at 660 cmxe2x88x921, 893 cmxe2x88x921, 930 cmxe2x88x921, 953 cmxe2x88x921, 970 cmxe2x88x921, 982 cmxe2x88x921, 1010 cmxe2x88x921, 1033 cmxe2x88x921 1052 cmxe2x88x921, 1060 cmxe2x88x921, 1069 cmxe2x88x921, 1109 cmxe2x88x921 and 1169 cmxe2x88x921, 1251 cmxe2x88x921, 1338 cmxe2x88x921, 1498 cmxe2x88x921, 1544 cmxe2x88x921, 1603 cmxe2x88x921, 1637 cmxe2x88x921, 1664 cmxe2x88x921. The TGA FIG. 6b curve shows a gradual loss on drying of 1.3% up to 150xc2x0 C.
A further embodiment is a new crystalline Form G of alendronate sodium, having a powder X-ray diffractogram substantially as depicted in FIG. 7a, with characteristic peaks at 9.5xc2x10.2, 10.1xc2x10.2, 12.7xc2x10.2, 16.2xc2x10.2, 17.3xc2x10.2, 17.6xc2x10.2, 19.1xc2x10.2, 20.4xc2x10.2, 20.9xc2x10.2, 22.1xc2x10.2, 24.8xc2x10.2, 25.5xc2x10.2, 28.0xc2x10.2, 29.0xc2x10.2, 29.6xc2x10.2, 30.4xc2x10.2, 32.4xc2x10.2, and 32.8xc2x10.2 degrees 2 theta. Form G has significant IR bands as depicted in FIG. 7c at 665 cmxe2x88x921, 751 cmxe2x88x921, 856 cmxe2x88x921, 895 cmxe2x88x921, 913 cmxe2x88x921, 939 cmxe2x88x921, 1011 cmxe2x88x921, 1021 cmxe2x88x921, 1050 cmxe2x88x921, 1091 cmxe2x88x921, 1155 cmxe2x88x921, 1273 cmxe2x88x921, 1305 cmxe2x88x921, 1337 cmxe2x88x921, 1510 cmxe2x88x921, and 1639 cmxe2x88x921. The TGA curve, FIG. 7b, shows a loss on drying of 6.5% which indicates that the crystal form G contains a stoichiometric quantity of water corresponding to that of the monohydrate (expected loss on drying value: 6.2%). This TGA step is sharp and occurs at 195xc2x0 C. The relatively high temperature of dehydration implies that the water is bound tightly to the alendronate molecule. The dehydration step is immediately followed by another step due to decomposition. Due to the decomposition process that occurs adjacent to the dehydration, the conventional loss of drying method is not feasible, and for loss on drying determination the TGA is used.
Yet another embodiment is a new crystalline Form H of alendronate sodium, having a powder X-ray diffractogram substantially as depicted in FIG. 8a, with characteristic peaks at 9.2xc2x10.2, 13.0xc2x10.2, 14.2xc2x10.2, 15.0xc2x10.2, 17.1xc2x10.2, 20.7xc2x10.2, 22.0xc2x10.2, 22.4xc2x10.2, degrees two theta. Form H has significant IR bands, as depicted in FIG. 8c, of 664 cmxe2x88x921, 688 cmxe2x88x921, 722 cmxe2x88x921, 751 cmxe2x88x921, 863 cmxe2x88x921, 893 cmxe2x88x921, 918 cmxe2x88x921, 936 cmxe2x88x921, 984 cmxe2x88x921, 1010 cmxe2x88x921, 1036 cmxe2x88x921, 1052 cmxe2x88x921, 1092 cmxe2x88x921, 1157 cmxe2x88x921, 1273 cmxe2x88x921, 1303 cmxe2x88x921 and 1338 cmxe2x88x921, 1499 cmxe2x88x921, 1598 cmxe2x88x921, 1636 cmxe2x88x921, and 1664 cmxe2x88x921. The TGA curve FIG. 8b shows a sharp loss on drying of 3.7% at 170xc2x0 C.
All of sodium alendronate crystalline forms B, D, E, F, G and H contain water in the amount of 2.2 to 9.0% by weight.
The invention further provides a new hydrate form of alendronate sodium having a water content of 1.3% to 3.1%.
A further embodiment is a new hydrate form of alendronate sodium having a water content of 2.5% to 3.5%.
A further embodiment is a new hydrate form of alendronate sodium having a water content of 2.8% to 3.9%.
An additional embodiment is a new hydrate form of alendronate sodium having a water content of 3.2% to 5.8%.
Another embodiment is a new hydrate form of alendronate sodium having a water content of 5.1% to 7.0%.
A still further embodiment is a new hydrate form of alendronate sodium having a water content of 6.4% to 9.0%.
The invention also provides a new crystalline Form B of alendronate sodium, having a water content of 6.4% to 9.0%.
The invention further provides a new crystalline Form D of alendronate sodium, having a water content of 3.2% to 5.8%.
The invention further provides a new crystalline Form F of alendronate sodium, having a water content of 1.3% to 3.1%.
The invention further provides a new crystalline Form G of alendronate sodium, having a water content of 5.1% to 7.0%.
The invention further provides a new crystalline Form E of alendronate sodium, having a water content of 2.8% to 3.9%.
The invention further provides a new crystalline Form H of alendronate sodium, having a water content of 2.5% to 3.7%.
The invention provides a new monohydrate and a new dehydrate of alendronate sodium, having an X-ray diffractogram substantially as depicted in FIGS. 2a and 3a, accordingly, with characteristic peaks at 9.3xc2x10.2, 12.4xc2x10.2, 13.5xc2x10.2, 17.1xc2x10.2, 18.5xc2x10.2, 19.7xc2x10.2, 20.3xc2x10.2, 21.0xc2x10.2, 21.8xc2x10.2, 23.4xc2x10.2, 24.3xc2x10.2, 24.9xc2x10.2, 26.3xc2x10.2, 30.0xc2x10.2, and 34.4xc2x10.2 degrees 2 theta. Form C as depicted in FIGS. 2b and 3b has significant IR bands at 660 cmxe2x88x921, 745 cmxe2x88x921, 865 cmxe2x88x921, 913 cmxe2x88x921, 952 cmxe2x88x921, 966 cmxe2x88x921, 1017 cmxe2x88x921, 1046 cmxe2x88x921, 1128 cmxe2x88x921, 1174 cmxe2x88x921, 1235 cmxe2x88x921, 1340 cmxe2x88x921, 1402 cmxe2x88x921, 1544 cmxe2x88x921, 1606 cmxe2x88x921, and 1644 cmxe2x88x921. The TGA curve of the monohydrate Form C (FIG. 2b shows a loss on drying of 5.6% which implies that the crystal Form C contains a stoichiometric quantity of water close to that of the monohydrate (expected loss on drying value: 6.2%). The TGA curve of the dehydrate Form C (FIG. 3b) shows a sharp C loss on drying of 12.0% which implies that the crystal Form C contains a stoichiometric quantity of water corresponding to dehydrate (expected loss on drying value: 11.7%).
The present invention also relates to the method of preparing the compound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt having water content of 1.3% to 11.7% by reacting alendronic acid with one equivalent of sodium base in an aqueous organic solvent selected from the group consisting of. acetone, DMSO, DMF, acetonitrile, alcohols, polyalcohols and/or their ethers, pyridine, sulfolane, -methyl pyrrolidinone and dioxane.
The invention further provides a method for making Form D of alendronate sodium, comprising treating alendronic acid anhydrous in a lower alkanol with 1 equivalent of sodium base and 0 to 4 equivalents of water, followed by isolating the crystalline alendronate sodium Form D.
The invention further provides a method for making Form E of alendronate sodium, comprising treating alendronic acid, which is in anhydrous or monohydrate form, in a lower alkanol with 1 equivalent of sodium base and 9 to 15 equivalents of water, followed by isolating the crystalline alendronate sodium Form E.
The invention further provides a method for making Form F of alendronate sodium, comprising treating alendronic acid, in a lower alkanol with 1 equivalent of sodium base and 5 to 8 equivalents of water for anhydrous form and 3 to 20 equivalents of water for monohydrate form, followed by isolating the crystalline alendronate sodium Form F.
The invention further provides a method for making alendronate sodium monohydrate, comprising treating alendronic acid, in a lower alkanol with 1 equivalent of sodium base and water under the conditions described hereinafter, followed by isolating the alendronate sodium monohydrate.
The invention further provides a method for making Form G of alendronate sodium, comprising treating alendronic acid, in a lower alkanol with 1 equivalent of sodium base and water under the conditions described hereinafter, followed by isolating the crystalline alendronate sodium Form G.
Typical but not limiting conditions for preparing alendronate sodium Form G are as described in the following table:
The invention further provides a method for making Form G of alendronate sodium comprising treating any one or more of the crystal forms of alendronate sodium selected from the group which consists of Form B, Form C, Form D, Form E, Form F and Form H, in a lower alkanol, preferably ethanol, with 20-40 equilvalents of water under the conditions described hereinafter followed by isolating the crystalline alendronate sodium Form G.
The invention further provides a method for making Form G of alendronate sodium comprising treating alendronate monosodium trihydrate in a lower alkanol, preferably ethanol, with 25-35 equivalents of water under the condition described hereinafter, followed by isolating the crystalline alendronate sodium Form G.
The invention further provides a method for making Form G of alendronate sodium comprising treating any one or more forms of alendronate sodium salts preferably selected from the group consisting of monosodium, disodium, trisodium and tetrasodium salts, in a lower alkanol preferably ethanol with 20-40 equivalents of water under the conditions described hereinafter, followed by isolating the crystalline alendronate sodium Form G. In the event that the starting sodium salt is higher than monosodium (e.g. disodium, trisodium or tetrasodium) it is necessary to add an acid, preferably alendronic acid, in order to maintain the pH at about 4.4.
The invention further provides a method for making Form H of alendronate sodium, comprising treating alendronic acid, which is the anhydrous or monohydrate form, in a lower alkanol with one equivalent of sodium base and 25 to 35 equivalents of water, under the conditions described hereinafter, followed by isolating the crystalline alendronate sodium Form H.
The invention further provides a method for making Form B of alendronate sodium, comprising treating alendronic acid monohydrate in a lower alkanol with one equivalent of sodium base and 0 to 4 equivalents of water, followed by obtaining the crystalline alendronate sodium Form B.
The invention further provides a method for making alendronate sodium dihydrate comprising treating crystalline alendronate sodium trihydrate with an effective amount of drying agent followed by isolating the crystalline alendronate sodium dihydrate.
The invention further provides a method for making alendronate sodium monohydrate comprising treating crystalline alendronate sodium trihydrate with a sufficient amount of drying agent followed by isolating the crystalline alendronate sodium monohydrate.
The invention further provides a method for making alendronate sodium monohydrate comprising treating crystalline alendronate sodium dihydrate with a sufficient amount of drying agent followed by isolating the crystalline alendronate sodium monohydrate.
The invention further relates to a pharmaceutical composition which comprises alendronate sodium, having water content of 1.3 to 11.7 percent in a therapeutically effective amount, and a pharmaceutically acceptable carrier.
The invention further relates to a pharmaceutical composition which comprises alendronate sodium in Form B D, E, F, G and/or H in a therapeutically effective amount, and a pharmaceutically acceptable carrier.